Rxivist logo

Epstein-Barr Virus Induced Cytidine Metabolism Roles in Transformed B-cell Growth and Survival

By Jin-Hua Liang, Chong Wang, Stephanie Pei Tung Yiu, Bo Zhao, Rui Guo, Benjamin Gewurz

Posted 09 Jan 2021
bioRxiv DOI: 10.1101/2021.01.08.426018

Epstein-Barr virus (EBV) is associated with 200,000 cancers annually, including B-cell lymphomas in immunosuppressed hosts. Hypomorphic mutations of the de novo pyrimidine synthesis pathway enzyme cytidine 5 triphosphate synthase 1 (CTPS1) suppress cell mediated immunity, resulting in fulminant EBV infection and EBV+ central nervous system (CNS) lymphomas. Since CTP is a critical precursor for DNA, RNA and phospholipid synthesis, this observation raises the question of whether the isozyme CTPS2 or cytidine salvage pathways help meet CTP demand in EBV-infected B-cells. Here, we found that EBV upregulated CTPS1 and CTPS2 with distinct kinetics in newly infected B-cells. While CRISPR CTPS1 knockout caused DNA damage and proliferation defects in lymphoblastoid cell lines (LCL), which express the EBV latency III program observed in CNS lymphomas, double CTPS1/2 knockout caused stronger phenotypes. EBNA2, MYC and non-canonical NF-{square}B positively regulated CTPS1 expression. CTPS1 depletion impaired EBV lytic DNA synthesis, suggesting that latent EBV may drive pathogenesis with CTPS1 deficiency. Cytidine rescued CTPS1/2 deficiency phenotypes in EBV-transformed LCL and Burkitt B-cells, highlighting CTPS1/2 as a potential therapeutic target for EBV-driven lymphoproliferative disorders. Collectively, our results suggest that CTPS1 and CTPS2 have partially redundant roles in EBV-transformed B-cells and provide insights into EBV pathogenesis with CTPS1 deficiency.

Download data

  • Downloaded 440 times
  • Download rankings, all-time:
    • Site-wide: 87,116
    • In cancer biology: 2,569
  • Year to date:
    • Site-wide: 63,296
  • Since beginning of last month:
    • Site-wide: 58,069

Altmetric data


Downloads over time

Distribution of downloads per paper, site-wide


PanLingua

News